It is thought that certain actions of ethanol involve its interaction with endogenous opioids, including POMC-derived peptides such as beta- endorphin. To examine this possibility, we developed a sensitive and specific assay for POMC mRNA to obtain an estimate of the activity of the endorphinergic system in the mediobasal hypothalamus and the pituitary of rats exposed for ten days in an inhalation chamber to ethanol or water. This protocol causes dependence in the ethanol-treated group, as demonstrated by the presence of withdrawal seizures after cessation of treatment. While ethanol treatment did not affect POMC mRNA levels in the pituitary, levels were significantly reduced in the hypothalamus as compared to controls. These results suggest that some effects of ethanol, including its inhibition of the baroreflex (ethanol inhibits while beta- endorphin tonically facilitates the baroreflex), may involve the hypothalamic endorphinergic system. In other experiments we confirmed feed-back regulation of POMC mRNA by glucocorticoids in the anterior pituitary of rats, but found no evidence for such regulation in the neurointermediate lobe and in the mediobasal hypothalamus. Furthermore, we demonstrated that chronic treatment of rats with alpha-methyldopa causes an alpha2-receptor mediated increase in POMC mRNA in the mediobasal hypothalamus, as well as naltrexone-reversible hypotension. This provides further evidence for an endorphinergic component in the hypotension mediated by central alpha2-receptors. Earlier studies demonstrating that both GABA-A and GABA-B receptors in the brainstem are involved in the baroreflex inhibitory action of ethanol have been published.